Treatment of dry eye syndrome

ABSTRACT

Dry-eye syndrome and other dryness effects of glandular malfunction are treated orally by a combination which includes a source of omega-3 fatty acid, a source of omega-6 fatty acid, vitamin A, vitamin B6, a source of magnesium and a water-soluble antioxidant. The preparation preferably is contained in a capsule. In a preferred form of the preparation and of the method, the preparation also includes mucin and cold water fish oil. The fatty acids preferably are contained in blackcurrant seed oil, and the water-soluble antioxidant is preferably in the form of vitamin C.

BACKGROUND OF THE INVENTION

[0001] This invention concerns generally the treatment of disease, andmore particularly the treatment of human glandular function disordersinvolving oil and mucus secreting glands and/or tear secreting(lacrimal) glands leading to dryness in the eyes, mouth or other areas.

[0002] Dry-eye syndrome is a common condition affecting approximatelyone in five Americans. It is characterized by symptoms including dry,irritated eyes, excessively watery eyes, burning and stinging, a foreignbody sensation, and blurred vision. Despite the diverse causes of dryeye syndrome, in all dry eye conditions the ocular surface epitheliumundergoes squamous metaplasia, manifested by loss of goblet cells, mucindeficiency and keratinization. These changes result in tear filminstability, which leads to the clinical symptoms of dry eye syndrome.

[0003] Human tears are produced by the lacrimal glands. Tears aredistributed by blinking, undergo evaporation from the ocular surface,and drain through the nasal lacrimal duct. An abnormality in any ofthese processes can cause dry eye. For example, Sjogren's Syndrome iscaused by damage to the lacrimal gland, which disables the reflexaqueous tear production process. Meibomian gland dysfunction, or MGD,alters the oily layer in tears, causing increased evaporation. The tearscomprise three layers, only one of which is the aqueous saline layer. Alayer of mucin, a slimy substance produced by the goblet cells, coatsthe corneal epithelium. The aqueous tear layer, produced by the lacrimalgland and approximately 0.9% saline, floats on the mucin layer. Outsidethe aqueous tear layer is an oil layer which protects the tears, thisoil being produced by glands located in the eyelid. This oil is actuallyan aqueous-lipid mixture, a thin, fine film which floats on top of thetears and limits evaporation.

[0004] Essential fatty acids (EFAs) are critical to optimum ocularfunctioning. EFAs cannot be synthesized by the human body and thus mustbe obtained from the diet. The omega-6 essential fatty acid, linoleicacid, is of particular importance to dry eye syndrome. The body convertslinoleic acid into prostaglandin E1 (PGE1) in the following step-wisesequence: linoleic acid, gamma-linolenic acid (GLA),dihomo-gamma-linolenic acid, prostaglandin E1. It is important thatomega-3 fatty acids be in balance with the omega-6 fatty acids.

[0005] Enzymatic conversion of linoleic acid to PGE1 may be impaired bya wide variety of factors, including an insufficiency or imbalance offatty acid precursors; a deficiency of nutrient conversion factors;aging; viral infections; consumption of foods rich in trans-fatty acidsand saturated fats; and alcohol. Thus, a direct source of GLA must beprovided in many circumstances in order to form prostaglandin E1 forproper tear production.

[0006] Horrobin and others have suggested that an effective approach tothe treatment of dry eye disorders may be to address the biochemicalbasis of an intact tear film. See Horrobin D. F., Campbell A., McEwen C.G.: Treatment of the Sicca Syndrome and the Sjogren's Syndrome withE.F.A., Pyroxidine and Vitamin C. Prog Lipid Res 8(4): 253-4, 1981; andOxholm, P., Manthorpe R., Prause J. U., Horrobin D.: Patients withPrimary Sjogrn's Syndrome Treated for 2 Months With Evening PrimroseOil. Scand J Rheumatology 1986: 103-108. In this work the authorsevaluated the use of supplemental intake of the essential fatty acids,linoleic and gamma-linolenic acids, vitamin B6, and vitamin C to treatdry eye. These nutrients are necessary components of the pathway forbiosynthesis of PGE1, which is necessary for aqueous tear secretion bythe lacrimal gland. See also Horrobin U.S. Pat. No. 4,388,324 andRe31,386, and U.S. Pat. Nos. 3,993,775, 4,977,187, 5,677,335 and6,060,486.

[0007] However, the work of Horrobin et al., while it may have beeneffective to increase aqueous tear secretion via the lacrimal gland, didnot address all issues regarding dry eye syndrome. In many patients withdry eye syndrome, the function of the lacrimal glands is normal, withadequate aqueous tear production; it is one of the other tear layersdescribed above which is inadequate. Enhancement of the function ofthese other glands, or supplying the deficiencies exhibited by theglands, was not adequately addressed in the prior studies.

[0008] Most previous treatments for dry eye syndrome have involved thetopical application of eye drops, which can be required very frequentlyin some patients. However, in addition to the Horrobin patentsreferenced above, Urashima U.S. Pat. No. 6,060,486 and Robertson U.S.Pat. No. 5,677,335 (listed above) are directed to oral approaches to thetreatment of dry eye syndrome.

SUMMARY OF THE INVENTION

[0009] The treatment embodied in the present invention addresses all ofthe underlying cellular factors that may produce dry eye syndrome (orother glandular-related dryness), including deficiency of omega-3 EFAsand prostaglandin E1 (PGE1), ocular deficiency of vitamin A, andabnormal levels of mucus, glycoproteins produced by conjunctival gobletcells. The orally-administered preparation comprises a uniquecombination of biologically active ingredients. The preparation does notmerely treat symptoms of dry eye, as do prior topical lubricatingproducts or hypotonic solutions and mucolytic agents that can decreasesymptoms of excess mucin strands, or other additives that can help lowertension at the water-oil interfaces and mimic some actions of mucinnetwork. The treatment according to the invention addresses theunderlying causes of dry eye syndrome, rather than providing temporarypalliative measures. The invention addresses the biochemical basis of anintact tear film, treating the causative factors of dry eye syndrome andsupporting the body's natural tear formation.

[0010] In one preferred embodiment of the preparation and treatmentaccording to the invention, the preparation includes blackcurrant seedoil, as a source of both omega-3 and omega-6 fatty acids; pyridoxal5-phosphate, the active form of vitamin B6; ascorbic acid and ascorbilpalmitate (vitamin C); vitamin A; mucin; and magnesium, preferably inthe form of magnesium sulfate. The preparation preferably also includescod liver oil, as an additional source of omega-3 essential fatty acids.

[0011] One important aspect of the formulation of the invention, foreffective treatment, is the provision of the omega-3 fatty acids fromboth plant and fish sources, due to the synergistic combination of thetwo types of fatty acids from these difference sources.

[0012] These and other objects, advantages and features of the inventionwill be apparent from the following description of a preferredembodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0013] In a preferred embodiment of a preparation for treating dry eyesyndrome, and also for treating dryness in the mouth, female vaginaldryness or other glandular-related dryness, the preparation of theinvention includes the following components: Vitamin A (from retinylpalmitate) 1040 IU (or a range of about 200 to 5000 IU) Vitamin C (fromcalcium ascorbate) 90 mg (or at least about 50 mg) Vitamin B6 (frompyridoxal 5-phosphate) 6.3 mg (or a range of about 2.0 to 20 mg)Magnesium (from magnesium sulfate) 20 mg (or a range of about 10 to 50mg) Black Currant Seed Oil (or other 750 mg (or at least about plantsource providing gamma 300 mg) linolenic acid (GLA)) Mucin 150 mg (or arange of about 100 to 300 mg) Cod Liver Oil 1.6 mg (or a range of (orother cold water fish oil) about 0.5 to 3.0 mg)

[0014] This preparation preferably is administered to a patient twicedaily, advantageously taken with meals (it should be understood that theword “preparation” or “formulation” as used herein is intended to refercollectively to these substances and amounts whether taken separately bya patient or whether included in a single capsule or other ingestiblemedium).

[0015] The above is a preferred form of the treatment of the invention,but variations are possible. The above formulation addresses not onlythe adequate production of aqueous tears, the middle layer of a healthytear film on the eye, but also the slippery substances which comprisethe inner layer directly coating the epithelium and the outer oily layerover the aqueous tear layer, which helps prevent evaporation. The rangesindicated for the carious components are probable approximate limits asprojected from research and the applicants' knowledge of the functionalrole played by each substance.

[0016] The following is a discussion of the components of the aboveformulation.

[0017] Black Currant Seed Oil

[0018] Black currant seed oil contains both omega-3 and omega-6 fattyacids, as well as gamma-linolenic acid (GLA). These EFAs regulatemembrane fluidity and membrane function, serve as precursors toeicosanoids (prostaglandins, thromboxanes, and leukotrienes), exhibitenzyme-like activities, and serve as cofactors for enzymes, helping toprevent the drying and atrophy of tear glands. Research findsstatistically significant improvement in overall ocular scores inpatients with Sjogren's syndrome treated with linoleic acid andgamma-linolenic acid (GLA) over control groups. Omega-3 fatty acid,omega-6 fatty acid and GLA together make up about 31% of black currantseed oil. Thus, the preferred formulation contains at least about 94 mgof these three components together, and preferably contains about 235 mgof these.

[0019] Omega-3 Fatty Acid

[0020] Omega-3 fatty acid is an “essential” fatty acid, required inamounts of about 500 mg daily. Commercially it is derived from fish oil,microalgae, and certain plant foods such as flax seed, borage, eveningprimrose and currant oils.

[0021] Omega-3 and omega-6 fatty acids are both essential, but omega 3sare more depleted in American diets and therefore more important innutritional supplements. Dietary omega-3 EFAs come from both animal andplant sources. The major source of the particular omega-3 fatty acid DHA(docosahexaeonic acid) is cold water fish such as salmon, tuna, cod,mackerel, sardines and trout. Omega-3s are also found in walnuts, canolaoil, flaxseed and green leafy vegetables.

[0022] Omega-3s reduce formation of the hormonelike prostaglandins whichtrigger inflammatory processes. They do this by replacing excessiveomega-6 fatty acids, which readily oxidize into free radicals. In mostAmericans the omega-6s overwhelm and dominate activity in cells, andomega-3s help restore the balance. Animal studies have shown thatomega-3 fatty acids increase antioxidant enzyme activity and omega-6oils reduce it. Omega-6s are essential, but they must be in balance withomega-3s (similarly to the needed balance between HDL and LDL in theblood).

[0023] Pyridoxal 5-Phosphate (Vitamin B6)

[0024] Pyridoxal 5-phosphate is the active form of vitamin B6. It isnecessary for the normal activity of the enzyme delta-6-desaturase,which converts cis-linoleic acid to GLA, and GLA into the precursor ofPGE1, dihomo-gamma-linolenic acid. Vitamin B6, or pyridoxal 5-phosphate,is thus a micronutrient cofactor supporting and enhancing conversion oflinoleic acid to gamma linolenic acid (GLA). Research using pyridoxal5-phosphate in combination with essential fatty acids and vitamin C hasdemonstrated improvement within two to six weeks in two thirds oftreated subjects.

[0025] Ascorbic Acid (Vitamin C) and Ascorbyl Palmitate

[0026] Vitamin C is required for the conversion ofdihomo-gamma-linolenic acid into prostaglandin E1, and thus is criticalfor tear production. Ascorbic acid in tears serves an antiflammatoryrole in the eye's defense system. Vitamin C could be replaced by anotherwater-soluble antioxidant, but vitamin C is preferred.

[0027] Vitamin A

[0028] Vitamin A regulates the proliferation and differentiation ofcorneal epithelial cells and preserves conjunctival goblet cells. It isrequired for the synthesis of mucin glyco-proteins in the eye. Adeficiency of vitamin A can result in abnormal epithelial cells in theeyelids, lacrimal glands, and conjunctiva. Vitamin A deficiency can alsoproduce abnormalities of the precorneal tear film and tear glands, andinduce the occurrence of dry eye syndrome. Vitamin A treatment has beenshown to reverse many of the underlying cellular changes that lead todry eye syndrome.

[0029] Mucin

[0030] The pre-ocular tear film is a complex biochemical fluid producedby the lacrimal glands and epithelial cells on the ocular surface. Thesymptoms of dry eye syndrome may result from deficiencies anddisturbances of the mucin network. For example, aqueous teardeficiencies lead to the ocular surface disorder, keratoconjunctivitissicca (Sicca), a dry eye syndrome. Sicca results from abnormal terminaldifferentiation of the ocular surface epithelium and is associated witha marked reduction in mucin production by the goblet cells, Theinclusion of mucin in the preferred form of the preparation is todirectly supply mucin glycoproteins for the maintenance of the mucinnetwork layer in the tear film. The mucin preferably is from an animalsource.

[0031] Magnesium

[0032] Magnesium is another essential micronutrient cofactor in theconversion of linoleic acid into GLA.

[0033] Cod Liver Oil

[0034] Cod liver oil is an additional source of essential fatty acids,specifically omega-3 fatty acid. Other cold water fish oils can be used,but cod liver oil is concentrated. As noted above, the cold water fishoil provides the important omega-3 fatty acid DHA.

[0035] The following examples illustrate the effectiveness of thepreparation outlined above, in the preferred formulation:

EXAMPLE 1

[0036] B. T., female, age 32 presented with history of red, dry, itchyeyes following yard work, felt to be due to exposure to allergens whileworking in yard. Diagnosis: allergic conjunctivitis with squamousmetaplasia.

[0037] Treatment: a preparation in the preferred form as describedabove, taken internally twice daily with meals.

[0038] Four week evaluation: Much improved corneal surface with greatertear film stability and reduced conjunctival injection.

EXAMPLE 2

[0039] M. G., female, age 28 reported dry eyes around the time of hermonthly periods, in addition to vague urinary complaints (burning,frequency). Diagnosis: hormonal imbalance with corneal squamousmetaplasia and mucin deficiency in addition to gynecologic symptoms.

[0040] Treatment: the preferred form preparation as described above,taken internally twice daily with meals.

[0041] Two week and six week evaluation: improvement of both ocular andgynecologic symptoms.

EXAMPLE 3

[0042] F. R., male, age 36, with history of long-term contact lens wear.Eyes felt dry, itchy, made worse with contact lens wear. Diagnosis:Inadequate ocular nutrition with recurrent erosion and keratinization.

[0043] Treatment: the preferred form preparation as described above,taken internally twice daily with meals.

[0044] Four week evaluation: Marked improvement of corneal surfacelubrication, reduced keratinization and no sign of recurrent erosion.

EXAMPLE 4

[0045] J. M., female, age 38. Immediate post-op Lasik. Reported dry,itchy eyes with visual blurring. Diagnosis: Neurovascular insufficiencywith interruption of interstitial fluid circulation.

[0046] Treatment: a preparation in the preferred form as describedabove, taken internally twice daily with meals.

[0047] Two and four week evaluation: Relief within 36 hours of dry itchyeyes. Blurring relieved after one week. Slit lamp biomicroscopy normalat two week evaluation.

EXAMPLE 5

[0048] S. W., male, age 57, post-cataract surgery with implantation ofSI 41 IOL (Multifocal IOL). Eyes dry, vision blurred with additionalhaloing and blur. Diagnosis: Stromal microedema with squamous metaplasiaand mucin deficiency.

[0049] Treatment: a preparation as described above, taken internallytwice daily with meals.

[0050] Two and four week valuation: Blur markedly diminished. Drynessmuch reduced. Halos still present but not as marked. Slit lampbiomicroscopy reveals essentially normal corneal appearance with minimalmetaplasia.

EXAMPLE 6

[0051] An ophthalmologist who is a foremost authority and world-renownedsurgeon in array implants, in which the natural accommodating lens ofthe eye is replaced by a multi-focal length lens array (multifocal IOL),underwent the procedure himself and had the natural lenses of both eyesreplaced by inter-ocular array implants. After surgery, as is typical,the distant vision was good, but the near vision was initially somewhatblurred and required several months to improve to full sharpness.Approximately one and one half years after the surgery, theophthalmologist's left eye exhibited some problems of distorted vision.This seemed to indicate the need for a further laser surgical procedurethat is required in approximately 10% to 50% of post-operative patientsreceiving the multifocal IOL. However, the ophthalmologist put himselfon the treatment as described above, using the preferred form ofpreparation and taking the same dosage twice daily with meals. Withintwo weeks, improvement was noted in the left eye. After one full monthof the treatment, the symptoms of distorted vision had fullydisappeared. After this full improvement, the ophthalmologist wanted toconfirm the effect was from the treatment and thus discontinued takingthe preparation. Within three to four days, the ophthalmologist's visionagain deteriorated, to the same condition experienced previously. A weeklater, the treatment was resumed and the symptoms again disappeared.Moreover, the ophthalmologist had a patient who underwent the sameimplantation of the multifocal IOL, and the patient experienced the sameeffect. Much after the surgery, the patient experienced distorted visionsimilar to that of the ophthalmologist. The ophthalmologist suggestedthe treatment using the preparation in its preferred form as describedabove, taken twice daily with meals. After a period of time similar tothat experienced by the ophthalmologist, the patient's vision markedlyimproved, and the distorted vision was corrected. After a further periodduring which the patient was on this treatment, the patient's supply ofthe preparation was depleted, and the patient went several days withoutthe treatment. He noticed the symptoms of distorted vision returning,obtained an additional supply of the preparation and resumed treatment,and the symptoms again disappeared and did not reappear as long as thetreatment was continued. The ophthalmologist observed that the majorcontrolling factor in how well a patient can focus at differentdistances using the multi-focal lens of an inter-ocular implant, is howwell the patient's cornea is functioning. The use of the preparationdescribed above helps assure that the cornea is functioning at peak andoptimal performance, and this supports the function of the array implantin all of its focal zones.

[0052] Patients taking the above preparation for a period of at leastseveral weeks have additionally reported increased salivary secretion,vaginal secretion and joint mobility.

[0053] The above described preferred embodiments are intended toillustrate the principles of the invention, but not to limit its scope.Other embodiments and variations to this preferred embodiment will beapparent to those skilled in the art and may be made without departingfrom the spirit and scope of the invention as defined in the followingclaims.

We claim:
 1. A method for treating insufficient glandular production oflubricating liquids in an individual, comprising: administering orallyto the patient a preparation including effective amounts of: a source ofomega-3 fatty acid, a source of omega-6 fatty acid, vitamin A,micronutrient cofactors effective to support and enhance conversion oflinoleic acid to gamma-linolenic acid, and a water-soluble antioxidant.2. The method of claim 1, wherein the preparation further includesmucin.
 3. The method of claim 1, wherein the micronutrient cofactorsinclude vitamin B6.
 4. The method of claim 1, wherein the water-solubleantioxidant comprises ascorbic acid.
 5. The method of claim 4, whereinthe preparation further includes mucin.
 6. The method of claim 1,wherein the sources of omega-3 fatty acid and omega-6 fatty acidcomprise blackcurrant seed oil.
 7. The method of claim 6, wherein thepreparation further includes cold water fish oil as a source of omega-3fatty acid.
 8. The method of claim 1, wherein the preparation furtherincludes cold water fish oil as a source of omega-3 fatty acid.
 9. Themethod of claim 8, wherein the preparation further includes mucin. 10.The method of claim 1, wherein the micronutrient cofactors includevitamin B6 and a source of magnesium.
 11. The method of claim 10,wherein the preparation contains at least about 1000 iu vitamin A; atleast about 6 mg vitamin B6; at least about 20 mg magnesium as magnesiumsulfate; and omega-3 fatty acid, omega-6 fatty acid and GLA in acombined amount of at least about 94 mg.
 12. The method of claim 11,wherein the water-soluble antioxidant is vitamin C, present in at leastabout 50 mg.
 13. The method of claim 11, wherein the preparation furtherincludes mucin, present in at least about 100 mg.
 14. The method ofclaim 13, wherein the preparation further includes cold water fish oil,present in at least about 0.5 mg, as a source of omega-3 fatty acid. 15.The method of claim 11, wherein the preparation includes blackcurrantseed oil as a source of both omega-3 and omega-6 fatty acids, the seedoil being present in at least about 300 mg.
 16. The method of claim 1,wherein the micronutrient cofactors include a source of magnesium. 17.The method of claim 1, wherein the preparation further includes GLA andwherein the various constituents of the preparation are present in atleast the following amounts: (a) omega-3 fatty acid, omega-6 fatty acidand GLA, a combined total of about 235 mg; (b) vitamin A, about 1040 iu;(c) vitamin C as the water-soluble antioxidant, about 90 mg; (d) vitaminB6 as a micronutrient cofactor, about 6.3 mg; and (e) magnesium asmagnesium sulfate as the micronutrient cofactor, about 20 mg.
 18. Themethod of claim 17, wherein the preparation further includes mucin, atleast about 100 mg.
 19. The method of claim 17, wherein the preparationfurther includes at least about 1.6 mg cold water fish oil.
 20. Themethod of claim 1, as a treatment for dry eye syndrome.
 21. The methodof claim 1, as a treatment for surgically-induced dry eye syndrome. 22.An orally-administered preparation for treating insufficient glandularproduction of lubricating liquids in an individual, comprising effectiveamounts of: a source of omega-3 fatty acid, a source of omega-6 fattyacid, vitamin A, micronutrient cofactors effective to support andenhance conversion of linoleic acid to gamma-linolenic acid, and awater-soluble antioxidant.
 23. The preparation of claim 22, furtherincluding mucin.
 24. The preparation of claim 22, wherein themicronutrient cofactors include vitamin B6.
 25. The preparation of claim22, wherein the sources of omega-3 fatty acid and omega-6 fatty acidcomprise blackcurrant seed oil.
 26. The preparation of claim 22, whereinthe preparation further includes cold water fish oil as a source ofomega-3 fatty acid.
 27. The preparation of claim 22, wherein themicronutrient cofactors include vitamin B6 and a source of magnesium.28. The preparation of claim 27, containing at least about 1000 iuvitamin A; at least about 6 mg vitamin B6; at least about 20 mgmagnesium as magnesium sulfate; and omega-3 fatty acid, omega-6 fattyacid and GLA in a combined amount of at least about 94 mg.